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United States Patent | 6,127,390 |
deSolms ,   et al. | October 3, 2000 |
The present invention is directed to compounds which inhibit prenyl-protein transferase (FTase) and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
Inventors: | deSolms; S. Jane (Norristown, PA); Lumma, Jr.; William C. (Pennsburg, PA); Shaw; Anthony W. (Lansdale, PA); Sisko; John T. (Lansdale, PA); Tucker; Thomas J. (North Wales, PA) |
Assignee: | Merck & Co., Inc. (Rahway, NJ) |
Appl. No.: | 164482 |
Filed: | October 1, 1998 |
Current U.S. Class: | 514/341; 546/274.1; 546/274.4; 546/275.1 |
Intern'l Class: | A61K 031/44; C07D 401/06 |
Field of Search: | 514/341 546/274.1,274.4,275.1 |
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______________________________________ DNA-CaPO.sub.4 precipitate for 10 cm. plate of cells Ras expression plasmid (1 .mu.g/.mu.l) 10 .mu.l DSE-SEAP Plasmid (1 .mu.g/.mu.l) 2 .mu.l Sheared Calf Thymus DNA (1 .mu.g/.mu.l) 8 .mu.l 2M CaCl.sub.2 74 .mu.l dH.sub.2 O 506 .mu.l 2X HBS Buffer 280 mM NaCl 10 mM KCl 1.5 mM Na.sub.2 HPO.sub.4 2H.sub.2 O 12 mM dextrose 50 mM HEPES Final pH = 7.05 Luminesence Buffer (26 ml) Assay Buffer 20 ml Emerald Reagent .TM. (Tropix) 2.5 ml 100 mM homoarginine 2.5 ml CSPD Reagent .RTM. (Tropix) 1.0 ml ______________________________________
__________________________________________________________________________ # SEQUENCE LISTING - - - - <160> NUMBER OF SEQ ID NOS: 26 - - <210> SEQ ID NO 1 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 1 - - Cys Val Ile Met 1 - - - - <210> SEQ ID NO 2 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 2 - - Cys Val Leu Leu 1 - - - - <210> SEQ ID NO 3 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 3 - - Cys Val Val Met 1 - - - - <210> SEQ ID NO 4 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 4 - - Cys Ile Ile Met 1 - - - - <210> SEQ ID NO 5 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 5 - - Cys Leu Leu Leu 1 - - - - <210> SEQ ID NO 6 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 6 - - Cys Gln Leu Leu 1 - - - - <210> SEQ ID NO 7 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 7 - - Cys Ser Ile Met 1 - - - - <210> SEQ ID NO 8 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 8 - - Cys Ala Ile Met 1 - - - - <210> SEQ ID NO 9 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 9 - - Cys Lys Val Leu 1 - - - - <210> SEQ ID NO 10 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 10 - - Cys Leu Ile Met 1 - - - - <210> SEQ ID NO 11 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 11 - - Cys Val Leu Ser 1 - - - - <210> SEQ ID NO 12 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C-terminus CAAX sequence - #of prenyl-protein transferase substrate - - <400> SEQUENCE: 12 - - Cys Ala Ile Leu 1 - - - - <210> SEQ ID NO 13 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: synthesized peptide substrat - #e for geranylgeranyl-protein transferase type - #I - - <400> SEQUENCE: 13 - - Gly Lys Lys Lys Lys Lys Lys Ser Lys Thr Ly - #s Cys Val Ile Met 1 5 - # 10 - # 15 - - - - <210> SEQ ID NO 14 <211> LENGTH: 86 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 14 - - tctcctcgag gccaccatgg ggagtagcaa gagcaagcct aaggacccca gc - #cagcgccg 60 - - gatgacagaa tacaagcttg tggtgg - # - # 86 - - - - <210> SEQ ID NO 15 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 15 - - cacatctaga tcaggacagc acagacttgc agc - # - # 33 - - - - <210> SEQ ID NO 16 <211> LENGTH: 41 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 16 - - tctcctcgag gccaccatga cagaatacaa gcttgtggtg g - # - # 41 - - - - <210> SEQ ID NO 17 <211> LENGTH: 38 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 17 - - cactctagac tggtgtcaga gcagcacaca cttgcagc - # - # 38 - - - - <210> SEQ ID NO 18 <211> LENGTH: 38 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 18 - - gagagaattc gccaccatga cggaatataa gctggtgg - # - # 38 - - - - <210> SEQ ID NO 19 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 19 - - gagagtcgac gcgtcaggag agcacacact tgc - # - # 33 - - - - <210> SEQ ID NO 20 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 20 - - ccgccggcct ggaggagtac ag - # - # 22 - - - - <210> SEQ ID NO 21 <211> LENGTH: 38 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 21 - - gagagaattc gccaccatga ctgagtacaa actggtgg - # - # 38 - - - - <210> SEQ ID NO 22 <211> LENGTH: 32 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 22 - - gagagtcgac ttgttacatc accacacatg gc - # - # 32 - - - - <210> SEQ ID NO 23 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 23 - - gttggagcag ttggtgttgg g - # - # - #21 - - - - <210> SEQ ID NO 24 <211> LENGTH: 38 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 24 - - gagaggtacc gccaccatga ctgaatataa acttgtgg - # - # 38 - - - - <210> SEQ ID NO 25 <211> LENGTH: 36 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 25 - - ctctgtcgac gtatttacat aattacacac tttgtc - # - # 36 - - - - <210> SEQ ID NO 26 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: completely synthesized nucle - #otide sequence - - <400> SEQUENCE: 26 - - gtagttggag ctgttggcgt aggc - # - # 24 __________________________________________________________________________